Targeting Host Kinases for Hepatitis C Treatment
Traditionally, treatment of viruses has focused on targeting the viral proteins, however recent research has given rise to the idea of treating viruses by targeting host factors. The most advanced of these for Hepatitis C virus (HCV) is Alispovir, currently in Phase III clinical trials, which inhibits the peptidyl-prolyl isomerase activity of cyclophilin A. Building on this idea, researchers from the Tokyo Metropolitan Institute of Medical Science are working to develop a small-molecule inhibitor of cyclin-dependent kinases as a novel treatment for HCV. Their work is published this month in Antiviral Research.
HCV is a causative agent of chronic hepatitis, and persistent HCV infection often leads to the development of severe liver diseases, including cirrhosis and hepatocellular carcinoma. As an estimated 170 million people worldwide are infected with HCV, the virus is an increasing concern for global public health. There are six different genotypes of HCV, with type 1 accounting for nearly 60% of global infections. The current standard therapy for HCV is a treatment of pegylated interferon and ribavirin. However this treatment can be ineffective for several of the HCV genotypes, including the most commonly occurring type 1. Furthermore, the treatment is often associated with serious side effects and high costs.
Hoping to develop a more comprehensive treatment, researchers focused on disrupting host mechanisms necessary for HCV replication. Specifically they focused on retinoblastoma protein (Rb) which plays a major role in controlling the G1 to S phase transition.
Early in G1, Rb binds to the E2F transcription factors and blocks the E2F transactivation domains, recruiting transcriptional co-repressors and resulting in the repression of E2F-responsive promoters. Given that S phase facilitates both replication and translation of HCV, Rb is a negative regulator of two mechanisms necessary for HCV replication. Rb, however, is inactivated during normal cell progression. Progression through the cell cycle requires growth signals that lead to the activation of several cyclin-dependent kinases (CDK). CDKs phosphorylate Rb at multiple sites to suppress the repressive function of Rb.
In order to restore the repressive function of Rb researchers tested several CDK inhibitors. Their results show that CDK inhibitors suppress HCV replication in vitro and in vivo. Furthermore, they identify an interphase CDK, CDK4, as a host factor that is required for efficient HCV replication, suggesting a highly specific potential target for HCV therapy. Ongoing work on development of CDK inhibitors as anticancer drugs could potentially be leveraged to accelerate the development of more effective HCV treatments. A recent review of targeting host factors for HCV treatment can be found here.
